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New study finds structures in the DNA that regulate gene expression

All our cells contain the same genetic information. Yet, our different tissues are made of different types of cells. In each specific cell, different genes are active at different times, creating an immense diversity and functions for each cell type. Now, a new study led by Sérgio de Almeida, group leader at the Instituto de Medicina Molecular João Lobo Antunes (iMM; Portugal) and published in the scientific journal eLife* discovered a new mechanism to regulate gene expression in cells. This discovery is implicated in the regulation of which genes are active at a certain time in a cell, crucial to define the cell type and function and could also be important in DNA damage, which is involved in diseases such as cancer.

While copying the information in the DNA to the messenger RNAs, by the process known as transcription, the DNA can come together with the new RNA molecule. This interaction forms structures called R-loops. These structures are formed naturally between the DNA and RNA and are important regulators of gene expression, but can also lead to DNA damage. “The R-loops are structures that resemble a shoelace loop and are formed when the RNA molecule binds to one of the strands of the DNA during transcription. These R-loops have important regulatory effects, but can damage the DNA when they persist if cells are not able to solve them”, explains Sérgio de Almeida, leading researcher of the work.

“When we were looking at the genome, we saw that R-loops occur more frequently in specific regions of the DNA that have an alteration usually associated to higher levels of transcription” starts to explain João Sabino, first author of the study, adding “the R-loops are more common in DNA sequences that are actively read by the cell machineries at a certain time and define the identity of the cell”.

Using embryonic stem cells in the lab, a type of cell that still has the potential to originate all different cell types, the researchers observed that the formation of these DNA-RNA structures is important to regulate the genes that are expressed. The formation of the R-loops in these regions of the DNA can be important to determine the fate and differentiation of the cells.

“Basically, they are implicated in the process by which a cell ends up as a heart cell, a neuron, a muscle, or any other cell! Besides the regulation of the fate of the cells, the R-loops could be also involved in other processes, says Sérgio de Almeida and adds: “Importantly, these “shoelaces” can damage the DNA if the cell machinery cannot solve them. Damage in the DNA molecules is a hallmark of different cancer diseases and is involved in cell dysfunction.”

This work was developed at iMM in collaboration with researchers from the Institute for Health and Bioeconomy and UCIBIO-REQUIMTE at the NOVA School of Science and Technology (Lisbon, PT). This study was funded by the EU Horizon 2020 Research and Innovation Programme, and national funds from the Portuguese Foundation for Science and Technology.

João C Sabino, Madalena R de Almeida, Patrícia L Abreu, Ana M Ferreira, Paulo Caldas, Marco M Domingues, Nuno C Santos, Claus M Azzalin, Ana Rita Grosso, Sérgio Fernandes de Almeida. Epigenetic reprogramming by TET enzymes impacts co-transcriptional R-loops. eLife 2022; 11:e69476 DOI:10.7554/eLife.69476